Derivatives of 3-oxo-4-hydroxythiophan and process for the manufacture thereof



Patented Mar. 2, 1948 DERIVATIVES F 3-0X0-4-HYDROXY- THIOPHAN .AND'PROCESS FOR THE MANUFACTURE THEREOF Paul Kari-er, Zurich, Switzerland,assignor to Hoffmann-La Roche Inc., Nutley, N. .I., a corporation of NewJersey No Drawing. Application August 26, 1944, Serial No. 551,443. InSwitzerland July 2, 1943 Section 1, Public Law 690, August 8, 1946Patent expires July 2, 1963 a 1 Derivatives of 3oxo-4-hydroxy-thiophan,carrying aliphatic substituents in position 2, thus corresponding toFormula 1 anon-o0 OH: H I

can be used as starting material for the manufacture of pharmaceuticallyemployable derivatives of the type of biotin; the substituent is (CH2);i-R, n being a numeral from 1 to 4 and R is selected from this groupconsisting of --OH, O-alkyl, CN, COOH and the functional derivatives ofthe latter.

It has been found that compounds of the Formula I can be obtained fromthiophan-3-onederivatives of the Formula II by the action of halogen andsubsequent hydrolysis of the resulting halogen-thiophanonederivativesIII:

CHr-CO CHB1C0 CECE-C0 (5 Br: (I: 6 H20 A) H, H -r H: H --r Ha H S S S IIIII I From the derivatives or 3-oxo-4-hydroxy-thiophan (I) dioximes ofthe Formula V are obtained by the action of hydroxy-amine, and osazonesof the Formula VI by the action of phenyl-hydrazine.

The new compounds represent intermediate products for the manufacture ofmedicinal preparations.

Errample 1 40 parts of water are poured over 2.8 parts by weight of2-(fi-carbohydroxy-ethyl)thiophan- 3-one (Formula VII) 1.0 parts byweight of calcium-carbonate are added and, while stirring at 0 C., 0.9part by volume of vaporous bromine are slowly passed into the solutionby a current of carbon-dioxide. The introduction of the bromine-vapourtakes about 2 hours. Thereupon, the liquid is diluted with a littlewater, saturated with sodium-chloride and left to stand for a few hours.2-(fl-carbohydroxy-ethyl) 4 hydroxy-thiophan-ti-one (Formula IX) therebyseparates in slightly yellowish crystals. After 8 Claims. (01. 260-329)recrystallisation from hot water the compound melts at 129-130 C.

CH2CO H, norncmcoon ----t ones-co V H, onomcmooon VIII anon-co n3nomomcoon The dioxime of compound 1x melts at 195- 196 C. Thecorresponding phenyl-osazone is a pale yellow compound. Its meltingpoint is not well defined; the compound decomposes after previoussintering above 120 0., whereby it melts with simultaneous evolution ofgas.

Example 2 7 parts by weight of Z-(deIta-methoxy-butyl) thiophan-B-one(Formula X), which boils at 102-103 C. under a pressure of 0.05 mm., aredissolved in a mixture of 20 parts by volume of methanol and 13 parts ofwater and brominated after addition of 3.7 parts by weight ofcalciumcarbonate by passing in 2.1 parts by volume of bromine in gaseousstate. The reaction-temperature remains at 0 C. during the wholebromination and the reaction-mixture is stirred during this process.After addition of a further part by weight of calcium-carbonate. thereaction-mixture is allowed to stand for 36 hours at 18 0., the methanolis then removed in vacuo,

0 excess calcium-carbonate dissolved by addition of the requiredquantity of dilute hydrochloric acid, whereupon the reaction-mixture isextracted with ether. After evaporation of the ether,

7.0 parts by weight of a yellow oil free from halogen remain behind, inwhich the crude hydroxyketone (Formula X1) is contained.

onPZo anon-o0 n, H(OH:)4O cm H. mompo on;

x xx

The dioxime of compound XI melts at 188-189 0., and the correspondingphenyl-osazone shows a melting-point of 141 C.

Example 3 25 partsby weight of Z-(delta-carbdhydroxybutyD-thiophanone-3are dissolved in'lGO parts by volume of methanol and then treated with70 parts by weight of water. While stirring and cooling with ice, 20parts by weight of gaseous bromine are passed in by means of a currentof carbon-dioxide. Further 70 parts of water are gradually added. Thebromine is immedi ately used up. The greater part of thehydrogen-bromide formed is bound by addition of cal cium-carbonate. Thesolution is continually kept acid to Congo paper. When all of thebromine is used up, the reaction-product has separated from the aqueousmethanol-solution. It is separated from the solvent and washed with 50percent. methanol. The crystalline 2-(de1tacarbohydroxy-butyD-3 oxo 4hydroxy-thiophan is pure after recrystallising twice from ethyl-alcoholand shows a melting-point of 117- 118 C. The compound shows a strongreductive power, when tested upon ammoniacal silver-nitrate solution. 1

I claim: Y

1. 2- (p-carbohydroxy-ethyl) -3-oxo-4-hydroxythiophan.

2. 2-(de1ta-methoxy-buty1) -3-oXo-4-hydroxythiophan. I

3. z-(delta-carbohydroxy butyl) -.3-oxo-4-hydroxy-thiophan 4. Processfor the manufacture of Z-(fi-carbohydroxy-ethyl)-3-oxo-4-hydroxy-thiophan, comprising halogenatingZ-(p-carbohydroxy-ethyl)- 3-oxo-thiophan and'subjecting thehalogeno-ketone formed to hydrolysis.

--(CH2) n--R wherein 'n is a'numeral from 1 to 4, and R is selected fromthe group consisting of OH, O-alkyl,

CN, 0001-1, and functional derivatives of COOH.

8. Process for the manufacture of the com pounds of claim 7, comprisinghalogenating 2-[ (CH2) n-R] -3-oxo-thiophan and subjecting thehalgeno-ketone formed to hydrolysis, n being a numeral from 1 to 4, andB being a member of the group consisting of OH, O-alkyl, CN, COOH, andfunctional derivatives of COOH.

PAUL KARRER.

REFERENCES CITED The following references are of record in the file ofthis patent:

Karrer et al., Uber Thiophanverbindungen V, Helv. Chim. Acta, vol. 27,1944, page 239. (Photostat in 260-4329.)

Certificate of Correction Patent No. 2,436,865. March 2, 1948. PAULKARRER It is hereby certified that errors appear in the printedspecification of the above numbered patent requiring correction asfollows: Column 1, line 2, for the word substituents read substituents(X); line 5, for that portion of the formula reading RICO,

( an read ('JHX' line 10, for substituent read substituent X; line 12,for this group read the group; lines 20 to 22 inclusive, in theformulae, three occurrences, for

00" d CO (in r mx line 28, for hydroxy-amine read [zydroxyl-amz'ne;lines 33 to 35 inclusive, for that portion of Formulae V and VI reading"o-- c c- -o an, an read 3311; tax

\S/ \S/ and that the said Letters Patent should be read with thesecorrections therein that the same may conform to the record of the casein the Patent Oifice.

Signed and sealed this 25th day of May, A. D. 1948.

THOMAS F. MURPHY,

Assistant Oonmissioner of Patents.

